Desferrithiocin derivatives and methods of use thereof

• US 20060211746A1
• Filed: 03/02/2006
• Published: 09/21/2006
• Est. Priority Date: 09/09/2003
• Status: Active Grant

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Inventors: Bergeron, Raymond J. Jr.
• Granted Patent: US 8,604,216 B2
• Time in Patent Office: Days
• US Class Current: 514/365
• CPC Class Codes: C07D 277/12 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

Compounds represented by structural formulas such as Structural Formula (I): are highly efficient in clearing excess iron from an organism. The invention also discloses methods of treating conditions such as metal overload, oxidative stress, and neoplastic and preneoplastic conditions.

Claims

1. A compound represented by Structural Formula (I), (II), or (III):

wherein;

R₁ is —

H or an acyl group;

R₂ and R₃ are each independently —

H, an alkyl group, or an acyl group;

R₄ and R₅ are each independently —

H, an alkyl group, or —

OR₁₁;

R₆, R₇, and R₈ are each independently —

H or an alkyl group;

R₉ is —

OR₁₂ or —

N(OH)R₁₃;

R₁₀ is —

H or an alkyl group;

R₁₁ is an alkyl group or an acyl group;

R₁₂ is —

H or an alkyl group; and

R₁₃ is an alkyl group,

R₁₄ is an alkyl group;

m is an integer from 1 to 8; and

Z is

 

or a salt, solvate or hydrate thereof.

2. The compound of claim 1, wherein the compound is represented by Structural Formula (I):

3. The compound of claim 2, wherein R₉ is —

OR₁₂.

4. The compound of claim 3, wherein R₈ is —

H or —

CH₃.

5. The compound of claim 4, wherein R₆ and R₇ are independently —

H or —

CH₃.

6. The compound of claim 5, wherein R₄ and R₅ are each —

H.

7. The compound of claim 6, wherein R₂ and R₃ are independently —

H or —

CH₃.

8. The compound of claim 1, wherein the compound is represented by one of Structural Formulas (IV)-(XI):

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I), (II), or (III):

wherein;

R₁ is —

H or an acyl group;

R₂ and R₃ are each independently —

H, an alkyl group, or an acyl group;

R₄ and R₅ are each independently —

H, an alkyl group, or —

OR₁₁;

R₆, R₇, and R₈ are each independently —

H or an alkyl group;

R₉ is —

OR₁₂ or —

N(OH)R₁₃;

R₁₀ is —

H or an alkyl group;

R₁₁, is an alkyl group or an acyl group;

R₁₂ is —

H or an alkyl group; and

R₁₃ is an alkyl group,

R₁₄ is an alkyl group;

m is an integer from 1 to 8; and

Z is

 

or a pharmaceutically acceptable salt, solvate or hydrate thereof

10. The pharmaceutical composition of claim 9, wherein the compound is represented by Structural Formula (I):

11. The pharmaceutical composition of claim 10, wherein R₉ is —

OR₁₂.

12. The pharmaceutical composition of claim 11, wherein R₈ is —

H or —

CH₃.

13. The pharmaceutical composition of claim 12, wherein R₆ and R₇ are independently —

H or —

CH₃.

14. The pharmaceutical composition of claim 13, wherein R₄ and R₅ are each —

H.

15. The pharmaceutical composition of claim 14, wherein R₂ and R₃ are independently —

H or —

CH₃.

16. The pharmaceutical composition of claim 9, wherein the compound is represented by one of Structural Formulas (IV)-(XI):

17. A method of treating a pathological condition responsive to chelation or sequestration of a trivalent metal in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound represented by Structural Formula (I), (II), or (III):

wherein;

R₁ is —

H or an acyl group;

R₂ and R₃ are each independently —

H, an alkyl group, or an acyl group;

R₄ and R₅ are each independently —

H, an alkyl group, or —

OR₁₁;

R₆, R₇, and R₈ are each independently —

H or an alkyl group;

R₉ is —

OR₁₂ or —

N(OH)R₁₃;

R₁₀ is —

H or an alkyl group;

R₁₁ is an alkyl group or an acyl group;

R₁₂ is —

H or an alkyl group; and

R₁₃ is an alkyl group,

R₁₄ is an alkyl group;

m is an integer from 1 to 8; and

Z is

 

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

18-31. -31. (canceled)

32. A method of reducing oxidative stress in a subject in need of treatment therefor, comprising administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I), (II), or (III):

wherein;

R₁ is —

H or an acyl group;

R₂ and R₃ are each independently —

H, an alkyl group, or an acyl group;

R₄ and R₅ are each independently —

H, an alkyl group, or —

OR₁₁;

R₆, R₇, and R₈ are each independently —

H or an alkyl group;

R₉ is —

OR₁₂ or —

N(OH)R₁₃;

R₁₀ is —

H or an alkyl group;

R₁₁ is an alkyl group or an acyl group;

R₁₂ is —

H or an alkyl group; and

R₁₃ is an alkyl group,

R₁₄ is an alkyl group;

m is an integer from 1 to 8; and

Z is

 

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

33-39. -39. (canceled)

40. A method of treating a subject who is suffering from neoplastic disease or a preneoplastic condition, comprising administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I), (II), or (III):

wherein;

R₁ is —

H or an acyl group;

R₂ and R₃ are each independently —

H, an alkyl group, or an acyl group;

R₄ and R₅ are each independently —

H, an alkyl group, or —

OR₁₁;

R₆, R₇, and R₈ are each independently —

H or an alkyl group;

R₉ is —

OR₁₂ or —

N(OH)R₁₃;

R₁₀ is —

H or an alkyl group;

R₁₁ is an alkyl group or an acyl group;

R₁₂ is —

H or an alkyl group; and

R₁₃ is an alkyl group,

R₁₄ is an alkyl group;

m is an integer from 1 to 8; and

Z is

 

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

41-47. -47. (canceled)